PONE-D-19-17069

Acute kidney injury during an ultra-distance race

PLOS ONE

Dear Dr Jouffroy,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR:

Both reviewers raised important issues that should be carefully addressed to improve the quality of the manuscript.

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Paolo Cravedi

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors report on the temporal changes in kidney injury biomarkers before, during, and after an 80km ultra-distance race. The study was designed and conducted appropriately. The manuscript has potential and can benefit from some improved clarity with the results and associated conclusions. Additionally, the focus of the introduction and discussion can be expanded. A large focus of the introduction and discussion involves the AKI to CKD transition. Although this is a good point to make, the study had short term follow-up. The authors should expand these sections to include other exercise related AKIs, such as from “regular” marathons and spin classes. Several studies and numerous case reports have been published within the last few years, notably, one published in PLoS ONE. Additionally, Mansour et al. AJKD 2017, is an impactful study and should be discussed. The authors should add a discussion on the strengths and limitations of KIM-1 and NGAL, including the differences between blood and urine measurement.

Also, the novelty the authors make regarding their study of an ultra-distance race rather than a “regular” marathon is probably not as clinically significant as the authors make it out to be. This should be adjusted throughout the manuscript including the last two paragraphs of the discussion.

Minor comments:

The in-text tables and figure legends (pages 8-10) are confusing to follow and should be moved to the proper section according to the journal’s author instructions. Also, the landscape formatting on the later pages needs to be fixed.

Introduction

Page 4, line 3 – clarify what the 480,000 runners refers to specifically. Did 480,000 runners complete a marathon in that one year or in 2001, have 480,000 runners completed a marathon at some point in their life?

Methods

Page 5, line 8 – clarify what medical disease refers to. Is this specifically referring to chronic diseases? What about occasional headache or infections? Only systemic illness?

Page 5, lines 9-10 – The sentence needs to be rewritten. I believe the authors intent to say that the participants had free access to food and water during and after the race. “ad libitum”

The study protocol was approved in 2014, was this the same year the race occurred? The authors should mention the year of the race. At least they mentioned the weather that day.

Results

Page 8 line 12 – Clarify the sentence to specify mean time of the race is referring to “mean race completion time”

Table 1 – what is “Trial experience”?

Page 10, line 18 – elevated urine creatinine does not necessarily reflect a “high level of urine concentration”, which is determined from the measurement of specific gravity or osmolarity. The high urine creatinine may simply be reflective of the higher blood creatinine level. Measurement of urinary osmolarity and electrolytes in stored samples would provide additional insight into kidney function during and after the race.

How much of the rise in serum creatinine during the race is really a true reduction in CrCl vs. and increase in muscle release of creatinine? The authors should comment on this.

It would be interesting to see the breakdown of the kidney injury biomarkers by KDIGO AKI stage. Were the biomarkers more elevated in these participants?

Discussion

Page 14, line 4 – Although the authors comment on AKI to CKD transition in other sections, they should specify here safe for “short term” kidney function as their study followed patients up to 9 days after the race.

Page 14, lines 6-7 – This sentence is not accurate, The impact of long-distance running on kidney function has been studied. As mentioned earlier, the Mansour AJKD paper, and others.

Since the authors talk about acute dehydration leading to ATN in the discussion, they should mention that the clinical parameters in table 2 do reflect any clinical evidence of dehydration and supports their finding of no major kidney injury.

Page 15, line 7 – remove the word “the”

Page 15, line 8 – maybe hyaline and waxy casts are nonspecific but muddy brown urinary casts are not nonspecific and are indicative of tubular injury.

Page 15, lines 14-15 – the assumption that urine was highly diluted before the race is incorrect. There is no evidence to support this claim. Additionally, what does “huge fluid consumption” actually mean?

Reviewer #2: The Authors in their interesting work show that transient increase in creatinine is not accompanied to parallel increase of two urinary biomarkers of acute kidney injury (uNGAL/uCr and uKIM 1/uCr) (ultra-distance race) in trained athletes during intense physical effort.

Major criticisms

-The Authors show that uNGAL/uCr significantly decreases from baseline to day 9 after the physical effort, however in the discussion they state that “…all biomarker variation fully disappeared on day 9...” and “…urine levels of NGAL..were similar at 80 km and at baseline after correction for urine dilution status”. I believe that the decrease of uNGAL/uCr during the physical effort and at day 9 after the race deserves an appropriate discussion. Do the Authors have any data regarding the physical activity/diet in the short term before (ideally 7-10 days) and after the race ? Furthermore it would be interesting to compare baseline athletes’ uNGAL/uCr with healthy control population . Finally it has been previously reported that uNGAL/uCr increases in athletes after 60 kg ultramarathon ( Clin Chem Lab Med. 2012 Feb 14;50(9):1585-9. doi: 10.1515/cclm-2011-0954), please discuss (different population/analysis method?).

Minor criticism

- eGFR should be reported in Table 2

- I would suggest to report the number of subjects with blood test in Table 2 legend (as done by the Authors in Table 3 legend)

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Reviewer #1: Yes: Joshua Rein

Reviewer #2: No

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PONE-D-19-17069R1

Acute kidney injury during an ultra-distance race

PLOS ONE

Dear Dr Jouffroy,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the final minor points raised during by Reviewer 1.

================================

We would appreciate receiving your revised manuscript by Oct 04 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Paolo Cravedi

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I thank the authors for their revisions that adequately addressed my major concerns. I have several additional comments/suggestions to further improve the manuscript for publication.

I appreciate the authors’ clarification regarding the novelty of their study in comparison to prior studies. The authors should add a sentence or two introducing what trail running is as explained in their response to my first comment. They can include aspects such as terrain, running surface, flat vs. hills, carry extra weight, and make a comparison with marathons to help clarify and explain differences in the races.

Throughout the manuscript, the authors should emphasize “ultra-distance” when referring to the race rather than “long-distance” to distinguish from marathons.

Authors use the words running where in some sentences, race would be the more appropriate word. The sentences can be reworded so that running also fits if the authors prefer to use that word. Page 3 lines 4 and 5 – “biomarker injury while running” or “biomarker injury during the race”

Temporal seems to be a more appropriate word than kinetic when describing changes in biomarkers over time. Kinetic refers more to the changes in the rate of something. The authors can consider calculating rates of change at each time point but I don’t think that would be of any clinical significance.

As some of the authors have previously published on changes in cardiac function during ultradistance racing, do the authors think the reduction in eGFR can be partially explained by cardiac strain? Also, the authors state in the discussion on page 18 line 22 that AKI may be prerenal. Besides extracellular volume depletion, it may be worth mentioning other potential mechanisms such effects on renal blood flow by the sympathetic nervous system, and antidiuresis from vasopressin release in response to stress/pain. May be worth commenting on to build the discussion but not critical.

Page 5 line 3 - As the authors discuss recent trends in increasing race distance in several parts of the manuscript, they should consider using a more recent reference than the one used from 2001.

Page 5 line 2 and line 10 – fix the use of two vs. 2

Page 5 line 24 – clarify that “before and after” is referring to the race

Page 6 line 3 – blood and urine samples were also collected before the race.

Did participants exclusively drink water or could some have consumed sports drinks? Might be worth discussing the association with kidney injury and rehydration with sugar sweetened beverages if participants did in fact have access to it.

It is more appropriate to use the word “chloride” rather than “chlorine” in the text and tables.

Page 12 lines 9-10 – Myoglobin increased from 34 to 2761, if not statistically significant, this increase may possibly be of some clinical significance. Although not massively elevated, do the authors believe this elevation could have contributed to any reduction in eGFR?

Page 14 lines 12-16 – Awkward sentence structure. These sentences would benefit from English editing.

Page 18 line 23 - If the hypothesis is that free access to food and water limited the kidney injury, it is safe to say on page 18 lines 12-13 that suggesting dehydration and antidiuresis?

Page 19 line 21 – ultraendurance races do in fact have considerable effects to kidney function such as, as the authors state, antidiuresis. However, it would be more accurate to state that ultra-endurance races specifically have no impact on acute kidney injury.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Acute kidney injury during an ultra-distance race

PONE-D-19-17069R2

Dear Dr. Jouffroy,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Paolo Cravedi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

"Temporal" is an adjective. As a noun, it refers to the temples of the skull.

In the present paper, "temporal" should be used in expressions such as, for instance, "temporal changes" or "temporal variations".

Reviewers' comments: